Asthma, rhinitis, other respiratory diseases

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1 Step-down therapy with low-dose fluticasone-salmeterol combination or medium-dose hydrofluoroalkane 134a beclomethasone alone Stephen J. Fowler, MBChB, Graeme P. Currie, MBChB, and Brian J. Lipworth, MD Dundee, Scotland Background: Options for step-down therapy include use of inhaled corticosteroids alone or in combination with a longacting β 2 -agonist. Objective: We sought to evaluate step-down therapy with a fluticasone propionate-salmeterol (FP-SM) combination administered through a dry powder inhaler (DPI; Advair Diskus) versus a medium dose of hydrofluoroalkane 143a beclomethasone dipropionate (HFA-BDP) administered through a breath-actuated pressurized metered-dose inhaler (QVAR Autohaler). Methods: Thirty-nine patients with uncontrolled moderate-tosevere asthma were treated with 1000 µg of DPI-administered BDP twice daily (DPI-BDP) for 4 weeks and then randomized to 200 µg of HFA-BDP twice daily (n = 20) or 100 µg of FP and 50 µg of SM twice daily (FM-SM; n = 19) for 8 weeks in a double-blind, double-dummy, parallel-group design. We measured the provocative dose of methacholine producing a 20% fall in FEV 1 (methacholine PD 20 ) as the primary outcome, with secondary outcomes being lung function, surrogate inflammatory markers, diary card responses, quality of life, and safety. Results: There was a 0.9 (95% confidence interval, ) doubling dose improvement in methacholine PD 20 comparing asthma before versus after DPI-BDP. HFA-BDP maintained this improvement, whereas FP-SM produced a further significant improvement, amounting to a 1.1 (95% confidence interval, ) doubling dose difference at 8 weeks for FP-SM versus HFA-BDP. Effects on FEV 1, peak expiratory flow, and quality of life (symptoms and emotions) were similar to those on methacholine PD 20, with a significant difference between FP-SM and HFA-BDP. Suppression of plasma and urinary cortisol and serum osteocalcin levels occurred with DPI-BDP, but values returned to baseline levels within 1 month of HFA-BDP or FP-SM administration. Conclusion: After high-dose inhaled corticosteroid, stepping From the Asthma and Allergy Research Group, Department of Clinical Pharmacology and Therapeutic, Ninewells Hospital and Medical School, University of Dundee, Dundee. Supported by a University of Dundee Anonymous Research Grant. Received for publication December 10, 2001; accepted for publication February 24, Reprint requests: Brian J. Lipworth, MD, Asthma and Allergy Research Group, Department of Clinical Pharmacology and Therapeutic, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom Mosby, Inc. All rights reserved /2002 $ /81/ doi: /mai down with the combination inhaler conferred further improvements in bronchoprotection, bronchodilatation, and clinical control, but not inflammatory markers, compared with that seen with a medium dose of inhaled corticosteroid. (J Allergy Clin Immunol 2002;109: ) Key words: Asthma therapy, bronchial hyperreactivity, fluticasone propionate, salmeterol, beclomethasone Current guidelines suggest that optimal control of patients with moderate-to-severe asthma is best achieved by first treating with high-dose inhaled corticosteroids and then stepping down to a level of therapy appropriate to the individual. 1 For patients with moderate-to-severe asthma not controlled by inhaled corticosteroids, there are 2 options available: either further increase the dose of inhaled corticosteroids or add second-line nonsteroidal therapy, such as a long-acting β 2 -agonist. To date, most studies comparing these 2 treatment options have concentrated on outcome measures, such as exacerbations, bronchodilation, reliever use, and symptom control, and have shown the addition of a longacting β 2 -agonist to produce equal or superior control compared with that achieved by doubling the dose of inhaled corticosteroids. 2-4 Important contributory factors in asthma exacerbations are bronchial hyperresponsiveness and asthmatic inflammation, which have been given little attention in previous studies. Subgroup analyses of 2 separate studies have shown no difference in bronchial responsiveness with 1000 µg of beclomethasone dipropionate (BDP) plus salmeterol (SM) versus 2000 µg of BDP alone 5 and no difference in sputum eosinophils comparing 200 µg of budesonide plus formoterol versus 800 µg of budesonide alone. 6 Furthermore, no studies have included a simultaneous and comprehensive evaluation of both systemic safety and efficacy. We therefore aimed to compare low-dose fluticasone propionate (100 µg) and SM (50 µg; FP-SM) administered by means of dry powder inhaler (DPI) twice daily with a medium dose of extrafine-particle hydrofluoroalkane 134a (HFA) BDP (200 µg) twice daily when stepped down from high-dose therapy. We decided to use the new HFA formulation of BDP, which, in one study, was found to be therapeutically microgram equivalent to HFA-FP 7 but with a much finer particle size and, consequently, more periph- 929

2 930 Fowler, Currie, and Lipworth J ALLERGY CLIN IMMUNOL JUNE 2002 Abbreviations used AQLQ: Asthma quality-of-life questionnaire BDP: Beclomethasone dipropionate CFC: Chlorofluorocarbon CV: Coefficient of variability DPI: Dry powder inhaler ECP: Eosinophil cationic protein FEF :Forced expiratory flow between 25% and 75% of fixed vital capacity FP: Fluticasone propionate HFA: Hydrofluoroalkane 134a PD 20 :Provocative dose producing a 20% fall in FEV 1 PEF: Peak expiratory flow SM: Salmeterol eral lung deposition. 8 We also elected to use a different DPI formulation of 1000 µg of BDP twice daily for the high-dose phase, so as not to bias the patients in favor of either of the subsequent randomized treatments. METHODS Patients Patients with moderate-to-severe asthma aged 16 to 70 years, who, at initial screening, were taking at least 800 µg of inhaled chlorofluorocarbon-bdp (CFC-BDP) or equivalent as monotherapy or at least 200 µg with second-line therapy, were screened for study entry. They had to fulfil the following inclusion criteria: FEV 1 of between 55% and 85% of predicted value; bronchodilator reversibility (to 400 µg of inhaled albuterol) of 15% for FEV 1 or forced expiratory flow between 25% and 75% of fixed vital capacity (FEF ); and provocative dose of methacholine causing a 20% fall in FEV 1 (methacholine PD 20 ) of less than 200 µg. They also had a second methacholine challenge performed at screening to assess protection afforded by 400 µg of inhaled albuterol. Patients were excluded if they had an asthma exacerbation, a course of oral prednisolone, or both within 3 months of study entry. Patients were also required to have diary card evidence over the previous month of using at least 2 puffs per day of rescue medication and having symptoms for at least 5 days per week. Patients who did not meet these criteria had their treatment tapered in a stepwise manner at 1- to 2- week intervals until either they were taking less than 200 µg of CFC-BDP or equivalent, in which case they were withdrawn from the study and returned to their prestudy treatment, or their β 2 -agonist use met the above criteria. Written informed consent was obtained from each patient before study entry, and the protocol was approved by the Tayside Committee on Medical Research Ethics. At initial screening, demographic data for the whole group of 39 patients were as follows: 20 male patients; mean ± SEM age of 44 ± 2 years; FEV 1 of 69% ± 1.3% of predicted value; FEV 1 reversibility (to 400 µg of albuterol) of 19% ± 1.7%; FEF of 38% ± 1.7% of predicted value; FEF reversibility of 33% ± 3.1%; geometric mean ± SEM methacholine PD 20 (before albuterol) of 38 ± 5.6 µg and methacholine PD 20 (after albuterol) of 500 ± 98 µg; and median daily inhaled steroid dose before the trial of 800 µg (interquartile range, µg) and at trial entry of 500 µg (interquartile range, µg). Twenty-two patients were taking CFC-BDP, 6 were taking HFA-BDP, 8 were taking FP, and 3 were taking budesonide. Study design The study consisted of three 1-month treatment blocks, with 4 monthly visits as follows. On study entry (visit 1), all patients entered a 1-month treatment period with 2000 µg of BDP per day administered through a DPI (DPI-BDP; Asmabec Clickhaler, 250 µg per actuation, 4 puffs twice daily; Medeva Pharma, Leatherhead, United Kingdom). They were also asked to use the supplied albuterol DPI (Asmasal Clickhaler, 100 µg per actuation; Medeva Pharma) instead of their usual rescue therapy during the study. Patients were then randomized at visit 2 in a double-blind, doubledummy, parallel-group design to receive either the FP-SM combination administered through a DPI (Advair 100 µg/50 µg Diskus, 1 puff twice daily; GlaxoWellcome, Uxbridge, United Kingdom) or HFA-BDP administered through a pressurized metered-dose inhaler (Qvar 100 µg Autohaler, 2 puffs twice daily; 3M Healthcare, Loughborough, United Kingdom). The dose counters on both the BDP and albuterol Clickhalers and the FP-SM Accuhaler facilitated checking of compliance and rescue inhaler use. At least 80% compliance with the prescribed dose was required for the data to be considered eligible for inclusion. Treatment packs included a 4-week diary card, a peak flowmeter, and written instructions on dosing and inhaler technique, which were reinforced verbally at each visit. Study visits The last dose of study drug was taken the night before each laboratory visit. Each patient attended the department at the same time of day, between 7 and 8:30 AM. They handed in a 10-hour overnight urine collection and their diary cards and inhalers from the last study period and then completed the asthma quality-of-life questionnaire (AQLQ). A cannula was inserted into an antecubital fossa vein, and the patient lay supine for 30 minutes. A 20-mL blood sample was then taken and divided into aliquots for early morning plasma cortisol measurement, and at visits 1, 2, and 4 only, serum eosinophil cationic protein (ECP) and osteocalcin levels were measured. At visits 1, 2, and 4, a bolus of 100 µg of human corticotropin-releasing factor (Clinalfa AG, Laufelfingen, Switzerland) was then administered, followed by a saline flush, and 30 minutes later, a further 5- ml blood sample was taken again for plasma cortisol. Finally, the following measurements were performed in order: exhaled nitric oxide; spirometry; and methacholine challenge. Patients then had the inhaler technique taught or reinforced as appropriate with placebo inhalers and the In-Check device (Clement Clarke, Harlow, United Kingdom) before having their next treatment pack dispensed. Measurements Patients were asked to perform and document morning and evening peak expiratory flow (PEF), symptom scores (0- to 3-point scale), and reliever use. Morning and evening symptom scores and reliever use were added to give a composite daily score. At each visit, patients were asked to complete the AQLQ, a sensitive, validated tool for measuring quality of life in asthma. 9 Its 32 questions (each having a 7-point scale) are grouped into 4 domains: activity limitations; symptoms; emotions; and exposure. An average mark is then calculated for each domain (out of 7), and the 4 domains are again averaged to give an overall score. A change in score of 0.5 or greater is considered clinically relevant. 10 Exhaled breath nitric oxide was measured according to recommended guidelines with an integrated LR2000 clinical real-time nitric oxide gas analyzer, with an accuracy of 2 parts per billion NO and a response time of 2 seconds (Logan Research, Rochester, United Kingdom). 11 Spirometry was carried out with a Vitalograph Compact spirometer (Vitalograph, Buckingham, United Kingdom) that was calibrated daily according to current American Thoracic Society guidelines. 12 Bronchial challenge with methacholine was performed by using the validated dosimetric method previously described by Beach et al. 13 All blood and urine assays were performed in duplicate. Plasma and urinary cortisol samples and serum osteocalcin were assayed

3 J ALLERGY CLIN IMMUNOL VOLUME 109, NUMBER 6 Fowler, Currie, and Lipworth 931 with a commercial RIA kit (Diasorin Ltd, Wokingham, United Kingdom). There was no cross-reactivity with either FP or BDP. The within- and between-assay coefficients of variability (CVs) for analytic imprecision were, respectively, 9.0% and 7.1% for plasma cortisol, 11% and 10.4% for urinary free cortisol, and 7.1% (within-assay only) for osteocalcin. Urinary creatinine was measured on a Cobas-bio autoanalyzer (Roche Products Ltd, Welwyn Garden City, United Kingdom); its within- and between-assay CVs were 3.7% and 3.1%. Serum ECP was also measured with an RIA kit (Pharmacia and Upjohn Diagnostics, Uppsala, Sweden), and its within-assay CV was 4.7%. Statistical analysis With a sample size of 18 in each randomized treatment limb and by using a parallel-group design, the study was designed to have at least 80% power to discriminate at least a 1-doubling-dose difference in methacholine PD 20 between groups (P <.05, 2-tailed). Statistical analysis was performed with the Statgraphics package (STSC Software Publishing Group, Rockville, Md). Data were compared by using multifactorial ANOVA, followed by multiplerange testing with the Bonferroni correction (95% confidence interval [CI], 2-tailed). After comparison of before and after 2000-µg DPI-BDP baselines, pooled data from visits 3 and 4 were analyzed for within- and between-treatment differences. A further analysis was also performed for between-treatment effects separately at visits 3 and 4. Significance was set at a P value of less than.05 (2- tailed) to not confound the overall α error. RESULTS Demographics Thirty-nine patients entered the steroid-optimization period. All were randomized, and no patients dropped out during the study, with 19 receiving FP-SM and 20 receiving HFA-BDP. Baseline characteristics for the patients in each parallel, randomized group before and after receiving high-dose DPI-BDP are shown in Table I. Efficacy data Bronchial hyperresponsiveness. Data on bronchial hyperresponsiveness are shown in Fig 1 and Table II. After treatment with DPI-BDP, geometric mean methacholine PD 20 values improved by 0.9 (95% CI, ) doubling doses. Patients subsequently treated with HFA- BDP maintained this improvement, whereas those receiving FP-SM experienced further improvement of 1.0 (95% CI, ) doubling doses. At 4 and 8 weeks, there was significant superiority for FP-SM versus HFA- BDP (ie, a difference of 1.1 [95% CI, ] and 1.1 [95% CI, ] doubling doses, respectively). Spirometry, diary card data, and AQLQ. Spirometry data are given in Fig 2 and Table II, diary card data in Table II, and AQLQ data in Table III. DPI-BDP improved FEV 1, FEF 25-75, and morning PEF compared with pretreatment values. These improvements were lost in patients randomized to HFA-BDP, but further improvement occurred with FP-SM. Improvements in overall AQLQ score were afforded before versus after DPI-BDP and were maintained in the group treated with FP-SM but not in those treated with HFA-BDP. In terms of clinically relevant changes (ie, 0.5), with DPI-BDP (from visit 1 FIG 1. Geometric mean ± SEM methacholine PD 20 before and after 1000 µg of DPI-BDP twice daily (visits 1 and 2, circles) and subsequent treatment (visits 3 and 4, triangles) with 100 µg of FP and 50 µg SM or 200 µg of HFA-BDP twice daily (squares). Significant differences are shown before versus after DPI-BDP and for FP-SM versus after DPI-BDP (visit 2) and versus HFA-BDP (visits 3 and 4). FIG 2. Mean ± SEM percent predicted FEV 1 before and after 1000 µg of DPI-BDP twice daily (visits 1 and 2, circles) and subsequent treatment (visits 3 and 4, triangles) with 100 µg of FP and 50 µg of SM twice daily or 200 µg of HFA-BDP twice daily (squares). Significant differences are shown before versus after DPI-BDP and for FP-SM versus after DPI-BDP (visit 2) and versus HFA-BDP (visits 3 and 4). baseline), 40% of patients improved, 7% deteriorated, and 53% did not change; for HFA-BDP (versus after DPI- BDP), 16% improved, 37% deteriorated, and 47% did not change; and for FP-SM (versus after DPI-BDP), 11% improved, 17% deteriorated, and 72% did not change. Inflammatory markers. Data on inflammatory markers are given in Table II. Tidal exhaled nitric oxide levels were not significantly altered by either treatment. Serum ECP was significantly attenuated before versus after DPI-BDP but then rose again with FP-SM. No significant difference was seen comparing HFA-BDP with the period after DPI-BDP. Safety data Safety data are given in Table II and Fig 3. All systemic adverse effect markers significantly decreased

4 932 Fowler, Currie, and Lipworth J ALLERGY CLIN IMMUNOL JUNE 2002 FIG 3. Geometric mean ± SEM for plasma cortisol before (filled symbols) and after (open symbols) stimulation with 100 µg of human corticotropin-releasing factor. Symbols are as per Fig 1. Significant differences are shown for before versus after DPI-BDP and for FP-SM and HFA-BDP at visits 3 and 4 versus after DPI-BDP. before versus after DPI-BDP but returned to pre DPI- BDP baseline levels with both randomized treatments, with no difference between FP-SM and HFA-BDP. DISCUSSION Our study demonstrated an additional benefit on the primary outcome of bronchial hyperresponsiveness with low-dose FP-SM versus a medium dose of HFA-BDP alone that was greater than the benefit conferred by 1 month s prior treatment with a high dose of inhaled DPI- BDP. This was associated with an improvement in FEV 1 and PEF, as well as some effects on quality of life. We deliberately elected to use a different type of BDP DPI for the initial high-dose phase, so as not to bias the subsequent randomized treatments. We decided not to compare FP-SM dry powder to twice the dose of FP dry powder, because we wanted to evaluate the anti-inflammatory effects of the extrafine HFA-BDP formulation, which has much greater lung deposition than FP dry powder. For example, the fine-particle fraction of HFA- BDP is 60% compared with 15% for FP-SM DPI. 8,14 Given the 4-fold greater respirable dose and BDP having half the corticosteroid potency as FP, this would extrapolate to 400 µg of HFA-BDP daily being approximately therapeutically equivalent to 800 µg of FP administered by means of DPI daily. Bronchial hyperresponsiveness is an important end point in comparative studies of long-term treatment strategies in asthma. Specifically, decreasing bronchial hyperresponsiveness has been shown to be associated with surrogate markers of airway inflammation 15 and airway remodeling. 16 Part of the improvement will have been due to the bronchoprotective effect of SM, although with chronic dosing this amounts to between a half to 1 doubling dose Measuring bronchial hyperresponsiveness to nebulized methacholine might only reflect changes in the larger airways because of more proximal deposition and not the small airways, where inflammation also occurs. 21 Hence it is possible that we might have missed some beneficial effects of HFA-BDP on the small airways. In this respect we did not measure differential effects of methacholine challenge on FEV 1 versus FEF Other studies have shown that HFA-BDP has a greater effect in reducing air trapping than CFC-BDP by using computed tomographic high-resolution scanning assessment before and after methacholine challenge. 22 The rationale for using 2000 µg of DPI-BDP was to ensure that the top of the dose-response curve was achieved for all patients during the initial high-dose phase. For example, with budesonide DPI in patients with moderate-to-severe asthma, the plateau in the curve for antiasthmatic efficacy was achieved at 800 µg daily. 23 Our patients showed deterioration in lung function when stepping down from 2000 µg of DPI-BDP to 400 µg of HFA-BDP. Thus 400 µg of HFA-BDP was probably suboptimal for our patients when given as monotherapy. This is consistent with previous data in which dose-related improvements in lung function were seen with HFA-BDP between 100 and 800 µg/d given over 6 weeks. 24 It is therefore interesting that 200 µg/d FP as the combination inhaler maintained the improvement in lung function after 2000 µg/d DPI-BDP. At first sight, this would suggest that the SM component was steroid sparing. However, closer inspection of the data for inflammatory surrogates, especially serum ECP, shows a numeric trend for loss of antiinflammatory efficacy with FP-SM compared with that seen with DPI-BDP. A higher dose of FP ( µg/d) in combination with SM might be a better compromise in terms of anti-inflammatory and bronchodilator efficacy for patients with moderate-to-severe asthma. Our patients were required to exhibit 15% or greater bronchodilator reversibility to albuterol as a standard inclusion criterion. One could argue that the study was therefore inadvertently biased in its patient selection toward finding a favorable response to another β 2 -agonist in SM. Indeed, for the primary end point, we showed a mean 3.8-doubling-dose improvement in methacholine PD 20 comparing before versus after albuterol at screening. It would have been revealing to have evaluated the protection conferred by albuterol at the end of the randomized treatments to assess the potential room for improvement in addition to that provided by HFA-BDP or FP-SM, given that SM has been shown to induce cross-tolerance to albuterol. 20,25 In retrospect, it would have also been informative to have evaluated bronchial hyperresponsiveness and lung function at the end of the study having washed out the effect of SM for 48 hours to see the effect of 200 µg of FP alone compared with that of 400 µg of HFA-BDP. However, because FP-SM is recommended for twice daily use, we thought that it was sensible to measure effects at the end of a 12-hour dosing interval. We attempted to assess effects on surrogate noninvasive markers of asthmatic inflammation. Methacholine challenge is one such marker but only weakly correlates

5 J ALLERGY CLIN IMMUNOL VOLUME 109, NUMBER 6 Fowler, Currie, and Lipworth 933 TABLE I. Data for patients before DPI-BDP (visit 1) and after DPI-BDP (visit 2) separately for each randomized treatment group (HFA-BDP and FP-SM) HFA-BDP (visit 1) FP-SM (visit 1) HFA-BDP (visit 2) FP-SM (visit 2) Efficacy data Methacholine PD 20 (µg) 40.7 ( ) 38.1 ( ) 75.6 ( ) 69.8 ( ) FEV 1 (L) 2.19 ( ) 2.21 ( ) 2.28 ( ) 2.40 ( ) FEV 1 (% predicted) 68 (64-72) 70 (65-74) 70 (66-74) 75 (71-79) FEF (L/s) 1.36 ( ) 1.39 ( ) 1.50 ( ) 1.59 ( ) FEF (% predicted) 35 (30-40) 37 (32-42) 38 (33-43) 42 (37-47) Morning PEF (L/min) 382 ( ) 384 ( ) 424 ( ) 403 ( ) Evening PEF (L/min) 390 ( ) 398 ( ) 421 ( ) 408 ( ) Symptom score (0-6) 1.1 ( ) 1.5 ( ) 0.7 ( ) 1.2 ( ) Reliever use (puffs/d) 3.8 ( ) 6.2 ( ) 2.4 ( ) 3.3 ( ) Tidal exhaled nitric oxide (ppb) 6.3 ( ) 7.7 ( ) 5.3 ( ) 5.8 ( ) Serum ECP (µg/l) 14.0 ( ) 20.6 ( ) 13.0 ( ) 15.4 ( ) Safety data 8 AM Plasma cortisol (nmol/l) 413 ( ) 388 ( ) 268 ( ) 279 ( ) Plasma cortisol after hcrf (nmol/l) 547 ( ) 527 ( ) 387 ( ) 398 ( ) Overnight urinary cortisol-creatinine (nmol/mmol) 3.98 ( ) 3.88 ( ) 1.87 ( ) 1.72 ( ) Serum osteocalcin (nmol/l) 5.6 ( ) 5.6 ( ) 4.5 ( ) 4.5 ( ) Results are given as means (95% CIs), except for methacholine PD 20, tidal exhaled nitric oxide, ECP, and safety data, which are shown as geometric means (95% CI). There were no significant differences between the groups. hcrf, Human corticotropin-releasing factor. TABLE II. Data for both randomized treatments before/after DPI-BDP and separately for subsequent effects of each randomized treatment group (HFA-BDP and FP-SM) Before DPI-BDP After DPI-BDP HFA-BDP FP-SM Efficacy data Methacholine PD 20 (µg) 39.4 ( ) 72.7 ( )* 71.2 ( )* ( )* FEV 1 (L) 2.20 ( ) 2.34 ( )* 2.26 ( ) 2.46 ( )* FEV 1 (% predicted) 69 (67-70) 73 (71-74)* 70 (68-72) 77 (75-79)* FEF (L/s) 1.37 ( ) 1.55 ( )* 1.46 ( ) 1.64 ( )* FEF (% predicted) 36 (34-38) 40 (38-42) 38 (35-40) 42 (40-45)* Morning PEF (L/min) 389 ( ) 414 ( )* 402 ( ) 434 ( )* Evening PEF (L/min) 402 ( ) 415 ( ) 408 ( ) 436 ( )* Symptom score (0-6) 1.3 ( ) 1.0 ( ) 1.0 ( ) 0.7 ( )* Reliever use (puffs/d) 5.1 ( ) 2.8 ( )* 3.5 ( ) 2.6 ( )* Tidal exhaled nitric oxide (ppb) 6.7 ( ) 5.5 ( ) 5.4 ( ) 6.7 ( ) Serum ECP (µg/l) 18.5 ( ) 14.1 ( ) 17.7 ( ) 20.8 ( ) Safety data 8 AM Plasma cortisol (nmol/l) 400 ( ) 274 ( ) 393 ( ) 413 ( ) Plasma cortisol after hcrf (nmol/l) 537 ( ) 398 ( ) 513 ( ) 522 ( ) 10-h Urinary cortisol-creatinine 3.85 ( ) 1.77 ( ) 3.97 ( ) 4.33 ( ) (nmol/mmol) Serum osteocalcin (nmol/l) 6.0 ( ) 4.5 ( ) 6.5 ( ) 6.8 ( ) Results are given as means (95% CIs), except methacholine PD 20, tidal exhaled nitric oxide, ECP, and safety data, which are shown as geometric means. Values for HFA-BDP and FP-SM are pooled for visits 3 and 4. *P <.05 versus pre DPI-BDP baseline values. P <.05 versus after DPI-BDP. P <.05 versus 400 µg of HFA-BDP administered by means of pressurized metered-dose inhaler. hcrf, Human corticotropin-releasing factor. TABLE III. Between-treatment differences in AQLQ scores DPI-BDP (before vs after) HFA-BDP vs after DPI-BDP FP-SM vs after DPI-BDP Change in AQLQ score Overall (0.24 to 0.80)* 0.34 ( 0.66 to 0.02) ( 0.25 to 0.43)* Activity limitation (0.09 to 0.55)* 0.34 ( 0.84 to 0.15) ( 0.24 to 0.76)* Symptoms (0.27 to 1.01)* 0.37 ( 0.87 to 0.13) ( 0.05 to 0.95)* Emotions (0.17 to 1.11)* 0.42 ( 1.05 to 0.20) ( 0.08 to 1.17)* Exposure (0.34 to 1.03)* 0.51 ( 1.12 to 0.10) ( 0.43 to 0.79)* Values are given as means (95% CIs). Values for HFA-BDP and FP-SM are pooled for visits 3 and 4. *P <.05 before versus after DPI-BDP. P <.05 versus after DPI-BDP. P <.05, FP-SM versus HFA-BDP.

6 934 Fowler, Currie, and Lipworth J ALLERGY CLIN IMMUNOL JUNE 2002 with more sensitive markers, except in steroid-naive patients, 26 and has a relatively steep dose response to inhaled corticosteroids at doses of up to 800 µg. 27 We are confident that in the present study a 2-month duration of each therapy was sufficient to achieve a nearmaximal effect on bronchial hyperresponsiveness. Indeed, there were no differences between effects on methacholine PD 20 after 4 and 8 weeks of treatment with either therapy. Another marker, exhaled nitric oxide, also has a very steep dose-response curve, with a plateau occurring at low doses of inhaled corticosteroids. 27,28 In our patients with unstable asthma, we did not believe a steroid washout period was ethically justified, and this study was designed to mirror real life, in which such a period would not have been used. Hence our patients already had low exhaled nitric oxide levels at baseline because of the suppressive effects of their previous inhaled corticosteroid therapy, and therefore this was not significantly affected by even the high-dose DPI-BDP. The other inflammatory marker we measured, serum ECP, significantly decreased after high-dose DPI- BDP, although it significantly increased again with combination therapy and showed a nonsignificant increase with HFA-BDP. Previous studies have shown SM to exhibit no effects on airway inflammatory cells or other surrogate inflammatory markers All surrogate markers of systemic adverse effects were, as expected, significantly suppressed with highdose DPI-BDP but returned to baseline levels within the first month of treatment with both study inhalers. This applied equally to plasma cortisol after stimulation with a physiologic 100-µg dose of human corticotropinreleasing factor. These latter data are especially reassuring because physiologic stimulation tests are very rarely performed in comparative studies but are likely to be the most sensitive and relevant markers to clinical practice. 33 The improvements afforded by FP-SM combination therapy over and above those seen with HFA-BDP reinforce previous studies that demonstrate the superiority of the former in terms of bronchodilation, symptoms, and quality of life, with no apparent safety implications, judging from the adrenal and bone markers that we measured. Our data would suggest it is unlikely that SM confers any additive anti-inflammatory effects in addition to those of low-dose FP. The improvements in bronchial hyperresponsiveness demonstrated with combination therapy might be explained by the functional antagonism against bronchoconstrictor stimuli conferred by SM. 34 In this respect the effects of SM on smooth muscle are complimentary to the anti-inflammatory effects of inhaled steroids. Whether SM s stabilizing activity on airway smooth muscle is responsible for reductions in exacerbations is unclear. We thank 3M Healthcare for supplying the Qvar and placebo Autohalers, as well as for financial assistance with the human corticotropin-releasing factor; Medeva Pharma for providing the Asmabec and Asmasal Clickhalers; L. Orr and W. Coutie for assistance in data collection and entry; and L. McFarlane for performing the biochemical assays. REFERENCES 1. Anonymous. The British guidelines on asthma management: 1995 review and position statement. Thorax 1997;52(suppl 1):S Shrewsbury S, Pyke S, Britton M. Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIAS- MA). BMJ 2000;320: Pauwels RA, Lofdahl CG, Postma DS, Tattersfield AE, O Byrne P, Barnes PJ, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. 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